The goals of our Center, Modifiers of FMR1-associated disorders: application of high throughput technologies, are targeted to the RFA research area to Advance the understanding of the pathophysiology of FMR1 Related Conditions. The completion of the proposed aims from the three research projects will lead to the identification of the genetic basis of variable expressivity or incomplete penetrance of FMR1-associated conditions by searching for modifying loci by whole genome sequencing (WGS) of 200 subjects in each of the three projects. Project A will focus on the variable expression of epilepsy among boys with fragile X syndrome (FXS), a co-morbid condition that occurs among 15% of affected boys and we speculate that variation elsewhere in the genome is responsible. Likewise, Project B will focus on the incomplete penetrance of fragile X tremor/ataxia syndrome (FXTAS) in men, a neurodegenerative disorder among those with the premutation (PM). Project C, the topic of this project proposal, focuses fragile X association primary ovarian insufficiency (FXPOl) which manifests in 20% of PM carriers as premature ovarian failure (POF), or cessation of menses prior to age 40. Project A will focus on FXS-associated comorbid conditions, targeting epilepsy. Epilepsy often occurs with intellectual disability and/or autism spectrum disorder (ASD) and many believe there may be shared susceptibility loci, although few have been identified. Since FXS increases the risk of epilepsy and ASD, the loss of FMRP may be considered a shared susceptibility locus but insufficient alone to trigger either comorbid conditions. Hence finding epistatic variants influencing epilepsy in FXS may identify shared modifiers between epilepsy and ASD. Epilepsy was also chosen as it is a precisely defined diagnosis and, unlike ASD for example, we can anticipate and therefore recognize at least one class of potential modifying loci based upon genes identified as leading to inherited seizure disorders, such as subunits of voltage-gated or ligand-gated ion channels. Therefore unraveling epilepsy-related modifying loci in FXS will not only significantly contribute to our understanding of FXS pathophysiology but may well uncover novel neurobiological interactions between FMRP loss and variation elsewhere in the genome.